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The Magnitude of the Warfarin-Amiodarone Drug-Drug Interaction Varies With Renal Function: A Propensity-Matched Cohort Study.

ABSTRACT: Amiodarone inhibits warfarin metabolism and is associated with major bleeding during warfarin therapy. Managing this drug-drug interaction (DDI) is challenging because of substantial interpatient variability in DDI magnitude. Because renal dysfunction induces changes in drug metabolism and protein binding that could alter cytochrome P450 inhibition mechanisms, we hypothesized that renal dysfunction alters the impact of the warfarin-amiodarone DDI. We tested this question in a propensity-matched cohort study of hospitalized patients with atrial fibrillation. Patients were queried from an electronic health record database. Renal function was estimated with creatinine clearance (CrCl). Warfarin response was measured with the warfarin sensitivity index (WSI), a dose-normalized international normalized ratio (INR) measure, and was modeled with multilevel mixed-effects linear regression. Time to supratherapeutic INR (> 4) was modeled using Cox regression. Propensity score matching resulted in 4,518 patients administered amiodarone and 4,518 controls. Amiodarone's effect on warfarin response varied threefold across the renal function range, increasing WSI by 36% in patients with normal renal function (CrCl 115 mL/minute), but by only 11.8% in patients with severe renal dysfunction (CrCl 15 mL/minute). Similarly, amiodarone had a strong effect in patients with normal renal function (hazard ratio (HR) 1.80; 1.23, 2.64), but a negligible effect on supratherapeutic INR hazard in patients with severe renal dysfunction (HR 1.01; 0.75, 1.37). These results suggest that renal function is a novel factor that explains substantial variability in the warfarin-amiodarone DDI. This information could inform warfarin dosage adjustment and monitoring and may have implications for the selection of oral anticoagulation agents in patients treated with amiodarone.

SUBMITTER: Miano TA

PROVIDER: S-EPMC7217725 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveTo evaluate maternal medical and perinatal outcomes associated with antipsychotic drug use in pregnancy.DesignHigh dimensional propensity score (HDPS) matched cohort study.SettingMultiple linked population health administrative databases in the entire province of Ontario, Canada.ParticipantsAmong women who delivered a singleton infant between 2003 and 2012, and who were eligible for provincially funded drug coverage, those with ≥ 2 consecutive prescriptions for an antipsychotic medication during pregnancy, at least one of which was filled in the first or second trimester, were selected. Of these antipsychotic drug users, 1021 were matched 1:1 with 1021 non-users by means of a HDPS algorithm.Main outcome measuresThe main maternal medical outcomes were gestational diabetes, hypertensive disorders of pregnancy, and venous thromboembolism. The main perinatal outcomes were preterm birth (<37 weeks), and a birth weight <3rd or >97th centile. Conditional Poisson regression analysis was used to generate rate ratios and 95% confidence intervals, adjusting for additionally prescribed non-antipsychotic psychotropic medications.ResultsCompared with non-users, women prescribed an antipsychotic medication in pregnancy did not seem to be at higher risk of gestational diabetes (rate ratio 1.10 (95% CI 0.77 to 1.57)), hypertensive disorders of pregnancy (1.12 (0.70 to 1.78)), or venous thromboembolism (0.95 (0.40 to 2.27)). The preterm birth rate, though high among antipsychotic users (14.5%) and matched non-users (14.3%), was not relatively different (rate ratio 0.99 (0.78 to 1.26)). Neither birth weight <3rd centile or >97th centile was associated with antipsychotic drug use in pregnancy (rate ratios 1.21 (0.81 to 1.82) and 1.26 (0.69 to 2.29) respectively).ConclusionsAntipsychotic drug use in pregnancy had minimal evident impact on important maternal medical and short term perinatal outcomes. However, the rate of adverse outcomes is high enough to warrant careful assessment of maternal and fetal wellbeing among women prescribed an antipsychotic drug in pregnancy.

Project description:ObjectivesTo examine the association of early invasive management of acute coronary syndrome with adverse renal outcomes and survival, and to determine whether the risks or benefits of early invasive management differ in people with pre-existing chronic kidney disease.DesignPropensity score matched cohort study.SettingAcute care hospitals in Alberta, Canada, 2004-09.Participants10,516 adults with non-ST elevation acute coronary syndrome.InterventionsParticipants were stratified by baseline estimated glomerular filtration rate and matched 1:1 on their propensity score for early invasive management (coronary catheterisation within two days of hospital admission).Main outcome measuresRisks of acute kidney injury, kidney injury requiring dialysis, progression to end stage renal disease, and all cause mortality were compared between those who received early invasive treatment versus conservative treatment.ResultsOf 10,516 included participants, 4276 (40.7%) received early invasive management. After using propensity score methods to assemble a matched cohort of conservative management participants with characteristics similar to those who received early invasive management (n=6768), early invasive management was associated with an increased risk of acute kidney injury (10.3% v 8.7%, risk ratio 1.18, 95% confidence interval 1.03 to 1.36; P=0.019), but no difference in the risk of acute kidney injury requiring dialysis (0.4% v 0.3%, 1.20, 0.52 to 2.78; P=0.670). Over a median follow-up of 2.5 years, the risk of progression to end stage renal disease did not differ between the groups (0.3 v 0.4 events per 100 person years, hazard ratio 0.91, 95% confidence interval 0.55 to 1.49; P=0.712); however, early invasive management was associated with reduced long term mortality (2.4 v 3.4 events per 100 person years, 0.69, 0.58 to 0.82; P<0.001). These associations were consistent among people with pre-existing reduced estimated glomerular filtration rate and with alternate definitions for early invasive management.ConclusionsCompared with conservative management, early invasive management of acute coronary syndrome is associated with a small increase in risk of acute kidney injury but not dialysis or long term progression to end stage renal disease.

Project description:BACKGROUND:Urological malignancy (UM) in patients with chronic kidney disease (CKD) is an added burden to their overall morbidity and mortality. UM is itself a common cause of CKD. Understanding the associations of UM with outcomes in advanced CKD can help in optimisation of the management of these patients. This study investigates the distribution and association of urological malignancy with outcomes (renal progression and mortality) in patients with advanced non-dialysis dependent CKD. METHODS:The study was conducted in 2637 of 3115 patients recruited in the Salford Kidney Study between the years 2002 and 2016. A comparative analysis was performed between 160 patients with UM (at baseline and incident) and 2477 patients with no malignancy. Cox-regression models and Kaplan-Meir estimates were used to explore the association between the presence of UM with mortality and renal outcome. Linear regression analysis was used to calculate the rate of progression of CKD in the groups. A 1:3 propensity score matched cohort of 640 patients was generated and utilised in the above analyses. RESULTS:4.4% had a history of UM at baseline with the annual incident rate being 0.37%. The site of malignancy was the kidney in 40% with comparable numbers for prostatic malignancy (39%). 70% (111/160) of UM patients had a medical cause as their primary diagnosis for CKD. Over a median follow up of 4?years, 34% (905) patients died. In the matched sample, the proportion of deaths was similar between the groups (UM 44% versus no malignancy 48%, p?=?0.36). 30% reached end-stage renal disease (ESRD) with no difference between the groups. In the Cox-regression model, UM did not prove to be a risk factor associated with either all-cause mortality (HR:1.03; CI: 0.79-1.35; p?=?0.81) or reaching ESRD (HR:1.12; CI: 0.80-1.58; p?=?0.49). The rate of decline in estimated glomerular filtration rate (eGFR) was similar between the groups (-?1.05 vs -?1.25?mL/min/1.73m2/year, p?=?0.31). CONCLUSIONS:There was no correlation observed between UM and all-cause mortality or ESRD. Medical causes of CKD have a significant influence on the outcomes in patients with UM, whereas the UM did not. Hence, a coordinated approach with early liaison between the urology and nephrology teams is needed in the management of UM patients with CKD.

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The Magnitude of the Warfarin-Amiodarone Drug-Drug Interaction Varies With Renal Function: A Propensity-Matched Cohort Study.

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